tbuckley/cabot-search huggingface dataset:
DIPG-18. Evaluating drug distribution in children with diffuse intrinsic pontine glioma (DIPG) treated with convection-enhanced drug delivery
Authors: Elwira Szychot, Dolin Bhagawati, Steven Gill, David Walker, Harpreet Hyare
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: There is currently no method for evaluating drug distribution and tumour coverage using the convection-enhanced drug delivery (CED) technique in diffuse midline glioma of the pons (previous DIPG). AIMS: To determine an imaging protocol that can be used to assess the distribution of infusate in children with DIPG treated with CED of carboplatin and sodium valproate. METHODS: 12 children with DIPG received between 4–18ml of infusate, through 2 pairs of catheters to encompass tumour volume on 2 days. Volumetric T2W and Diffusion Weighted Imaging (DWI) MRI sequences were performed before and after the first cycle of CED therapy and Apparent Diffusion Coefficient (ADC) maps were calculated. The tumour volume pre and post CED was automatically segmented (ITKSnap) on T2W and ADC on the basis of signal intensity. The ADC maps pre and post infusion were registered and subtracted (FSL) to visualize the infusate distribution. RESULTS: ADC and T2W demonstrated a significant (&amp;lt;0.001) change in mean tumour volume post-infusion (mean ADC volume pre: 19.8ml, post 24.4ml; mean T2W volume pre 19.4ml, post 23.4ml). A significant correlation (p&amp;lt;0.001) was observed for the difference in tumour volume and the actual infused volume (ADC, r=0.76, T2W, r=0.70). There was a significant increase (p&amp;lt;0.001) in mean ADC and mean T2W signal intensity ratio post-infusion, no significant correlation with infusion volume. Finally, pixel-by-pixel subtraction of the ADC maps pre and post infusion visually demonstrated high signal intensity, presumed infusate coverage of the tumour. CONCLUSIONS: Our study provides the preliminary evidence that measurement of change in tumour ADC and T2W MR sequences, has a potential value for quantifying the distribution of infusate delivered by the intermittent CED, which will facilitate the use of CED in future clinical trials.
Palliative care among metastatic breast cancer patients in the end-of-life period in the U.S.
Authors: Divya S. Subramaniam, Zidong Zhang, Alexandria Jenkins, Leslie J. Hinyard
Journal: Journal of Clinical Oncology (2022)

e13002 Background: Research has shown that palliative care improves the quality of end of life care, and lowers associated costs for cancer patients. The purpose of this study was to determine utilization of palliative care consult (PCC) on or after date of metastasis to date of death, the association of emergency department (ED), intensive care unit (ICU) and chemotherapies among metastatic breast cancer (MBC) patients in the United States. Methods: We conducted a retrospective study using the de-identified electronic medical record data from a national healthcare informatics provider and insurer between January 1, 2000 and December 31, 2018. The MBC patients (age ≥ 18 years) who were diagnosed with a secondary neoplasm after the index diagnosis of breast cancer and deceased in the period of data capture were included. The cohort was split into the PCC groups, patients who had received at least one PCC on or after the date of metastasis through date of death; and the non-PCC group. The ED, ICU and chemotherapy encounters since metastasis were defined by ICD-9/10, HCPCS or CPT codes per encounter records. We quantified the ED and ICU visits within two months of death; and the antineoplastic chemotherapies within one and two months of death. Time from metastasis to death and utilization of services were compared between the PCC and the non-PCC groups using Whitney U-test and Chi-squared test. Results: 979 deceased MBC patients had at least one PCC and 1,636 did not at all. Overall, average patient age at the last admission was 68.7+/-12.9 years. The median time from metastasis to death was 9 (2 – 24) years. More than half of them were Caucasian (79.8%) and nearly half from the Midwest region (47.1%). Between the two groups, age distribution was not significantly different, but the PCC patients were more likely to have shorter time to death (8 vs 10 years), be African American (12.8% vs 9.8%), reside in Midwest (52.9% vs 43.7%) and have experienced complications since metastasis except for acute cerebrovascular events. Compared to the non-PCC patients, the PCC patients were more likely to use ED (52.2% vs 22.2%), ICU (12.5% vs 13.4%) within two months of death, and to receive chemotherapy within one and two months of death (17.7% vs 13.9% and 12.9% vs 6.0%, respectively). Conclusions: Our study found that only 38% of BC patients received at least one PCC following date of metastatic diagnosis. Findings highlight the need to increase PCC among MBC patients immediately following diagnosis to ensure appropriate care is provided and utilized. Furthermore, educational and informational interventions will need to be developed to boost PCC utilization among MBC patients.
Gut microbiota signatures are associated with prostate cancer risk
Authors: S. Kalinen, T. Kallonen, M. Gunell, O. Ettala, I. Jambor, J. Knaapila, K.T. Syvänen, P. Taimen, M. Poutanen, C. Ohlsson, H.J. Aronen, H. Ollila, S. Pietilä, L.L. Elo, T. Lamminen, A.J. Hakanen, E. Munukka, P.J. Boström
Journal: European Urology (2022)
Effectiveness of mRNA vaccine boosters against infection with the SARS-CoV-2 omicron (B.1.1.529) variant in Spain: a nationwide cohort study
Authors: Susana Monge, Ayelén Rojas-Benedicto, Carmen Olmedo, Clara Mazagatos, María José Sierra, Aurora Limia, Elisa Martín-Merino, Amparo Larrauri, Miguel A Hernán, David Moreno, Manuel Méndez Díaz, Ismael Huerta González, Antònia Galmés Truyols, Ana Barreno Estévez, Valvanuz García Velasco, Mª Jesús Rodríguez Recio, José Sacristán, Montserrat Martínez Marcos, Eliseo Pastor Villalba, María José Macías Ortiz, Ana García Vallejo, Amaya Sánchez Gómez, Rocío García Pina, Aurelio Barricarte Gurea, Rosa Sancho Martínez, Eva María Ochoa, Mauricio Vázquez Cantero, Atanasio Gómez Anés, María Jesús Pareja Megía, Yolanda Castán, Manuel Roberto Fonseca Álvarez, Antonia Salvà Fiol, Hilda Sánchez Janáriz, Luz López Arce, María Ángeles Cisneros Martín, Frederic Jose Gibernau, Cesar Fernandez Buey, Katja Villatoro Bongiorno, Francisco Javier Rubio García, Fernando Santos Guerra, Jenaro Astray Mochales, Francisco Javier Francisco Verdu, Isabel García Romero, Rosa Oriza Bernal, Tomás Gómez Pérez, Salomé Hijano Villegas, Sergio Román Soto, Diana Gómez-Barroso, María Fé Lapeña, Virgilio Yagüe Galaup, Mercedes Alfaro Latorre, Marta Aguilera Guzmán, Belén Crespo Sánchez-Eznarriaga, Montserrat Neira León, Noemí Cívicos Villa
Journal: The Lancet Infectious Diseases (2022)
Locoregional Management of Early-Stage Breast Cancer
Authors: Meena S. Moran, A. Marilyn Leitch
Journal: Journal of the National Comprehensive Cancer Network (2022)

The latest version of NCCN Guidelines for Breast Cancer on locoregional management of early-stage breast cancer contains numerous updated recommendations, particularly focusing on management of the axilla, locoregional management after neoadjuvant therapy, and radiation delivery. Recommendations for axillary staging have been separated for patients who have undergone breast-conserving surgery and those who have had a mastectomy, creating 2 individual pathways. The section on locoregional treatment after neoadjuvant therapy has been reformatted; optimal management of this patient group continues to evolve. Lastly, specifics regarding the delivery and sequencing of radiotherapy have been updated.
NHS-Galleri Trial Design: Equitable study recruitment tactics for targeted population-level screening with a multi-cancer early detection (MCED) test.
Authors: Charles Swanton, Richard D Neal, Peter W. M. Johnson, Christina Clarke Dur, Stephanie A Hamilton, Nan Zhang, Harpal Kumar, Peter Sasieni
Journal: Journal of Clinical Oncology (2022)

TPS6606 Background: Cancer is a leading cause of premature death globally. Early detection can reduce cancer mortality by reducing the number of cancers diagnosed at a late stage. A blood-based MCED test (Galleri) was developed that can detect cancer signals and predict cancer origin with a single blood draw. The NHS-Galleri trial is a randomized controlled trial (RCT) assessing the clinical utility of this MCED test in a targeted screening population alongside current screening programs. Screening adherence is lower among certain individuals (eg, those with lower socioeconomic status), despite healthcare being free at the point of access in England. NHS-Galleri utilizes innovative strategies to optimize equity in study recruitment, with the goal of enrolling a representative sample. Methods: This pragmatic, blinded RCT is currently enrolling 140,000 asymptomatic participants by inviting ̃1.3 million residents aged 50-77 in select postcodes of England via the NHS DigiTrials service. Regions were selected to include areas of high cancer mortality, socioeconomic deprivation, and ethnic diversity; eligible participants will be identified from these regions. A variety of methods are employed to enroll a representative study population (defined as including a reasonable number of participants from all socioeconomic statuses and all major ethnic minority groups). These methods include the use of mobile phlebotomy clinics that facilitate access in economically deprived areas, monitoring of participant representativeness by postcode with dynamic adjustment of enrollment, providing interpreters and wheelchair accessibility, and targeted local campaigns. Blood will be collected at 3 annual visits (baseline, year 1, year 2) unless cancer is diagnosed. After baseline blood collection, participants will be randomized 1:1 to the intervention (blood sample analyzed by the MCED test) or control (blood sample stored for potential future MCED testing) arm. Only participants in the intervention arm with “cancer signal detected” will have results returned and be referred for investigations and possible treatment. Participants in the intervention arm without “cancer signal detected” and all in the control arm will remain blinded and return for annual visits. All participants will be reminded to continue guideline-based screening and report unusual/concerning symptoms to a doctor. The primary study objective is a significant reduction in the absolute numbers of stage III &amp; IV cancers diagnosed in the intervention versus control arm 3.5 years after randomization. Cancer-specific mortality will be assessed during trial follow-up. Exploratory endpoints include assessing the primary objective by participant age, gender, socioeconomic status, and ethnicity. Clinical trial information: ISRCTN91431511.
Trial in progress: A phase 2 study of sotorasib as first-line treatment in patients with stage IV non–small cell lung cancer (NSCLC) whose tumors harbor a <i>KRAS p.G12C</i> mutation (CodeBreaK 201).
Authors: Kathryn Cecilia Arbour, Monica Khurana, Tian Dai, Ferdinandos Skoulidis
Journal: Journal of Clinical Oncology (2022)

TPS9150 Background: Chemo-immunotherapy regimens represent a standard of care for the first-line treatment of metastatic NSCLC, yet clinical outcomes in patients bearing tumors that lack PD-L1 expression [PD-L1 Tumor Proportion Score (TPS) &lt; 1%)] or harbor a serine/threonine kinase 11 ( STK11) mutation remain poor. Sotorasib is a selective, irreversible small molecule KRAS G12C inhibitor that is approved for the treatment of patients with locally advanced or metastatic KRAS p.G12C-mutated NSCLC following failure of at least one prior line of systemic therapy and has previously demonstrated robust antitumor activity in subgroups of KRAS p.G12C mutant NSCLC with PD-L1 TPS &lt;1% and/or STK11 co-mutations. We hypothesized that sotorasib may represent an effective first-line therapy for subgroups of NSCLC patients who may have suboptimal chemo-immunotherapy outcomes and a high unmet clinical need. Methods: This phase 2, open-label, global study is designed to evaluate the efficacy and safety of sotorasib (960 mg or 240 mg daily) as first-line treatment in approximately 170 patients with KRAS p.G12C-mutated, metastatic NSCLC with PD-L1 TPS &lt;1% as determined by immunohistochemical assay and/or presence of STK11 mutation as determined by next-generation sequencing (NGS). Key eligibility criteria include patients with untreated metastatic NSCLC without active brain metastases. Patients will be stratified by known presence of STK11 mutation. The primary endpoint is objective response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary endpoints include disease control, duration of response, time to response, progression-free survival per RECIST 1.1, overall survival, safety and tolerability, and pharmacokinetic profile. Enrollment began in January 2022 and is ongoing. Contact Amgen Medical Information for more information. Clinical trial information: NCT04933695.
Gait and Cognitive Declines in Dementia—Double or Nothing
Authors: Joe Verghese
Journal: JAMA Network Open (2022)

Taya A. Collyer, PhD; Anne M. Murray, MD; Robyn L. Woods, PhD; Elsdon Storey, MBBS, DPhil; Trevor T.-J. Chong, MBBS, PhD; Joanne Ryan, PhD; Suzanne G. Orchard, PhD; Amy Brodtmann, MBBS, PhD; Velandai K. Srikanth, MBBS, PhD; Raj C. Shah, MD; Michele L. Callisaya, PhD
Necroptosis, unlike pyroptosis mediates right ventricular damage in pulmonary arterial hypertension
Authors: I Jarabicova, C Horvath, E Velasova, L Bies Pivackova, J Veteskova, J Klimas, P Krenek, A Adameova
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic The Slovak Research and Development Agency Introduction Necroptosis has been found to underlie myocardial damage in various pathological states, however its role as well as its potential interconnection to another cell damaging processes under conditions of pulmonary arterial hypertension (PAH) remains insufficiently understood. Purpose In view of these facts, we aimed to investigate the signalling of both necroptosis and pyroptosis in the lung and right ventricular (RV) tissue affected by PAH and we also examined the circulating levels of receptor-interacting protein kinase 3 (RIP3). Methods Male Wistar rats were administrated either vehicle (Control group) or monocrotaline (MCT) (60 mg/kg, s. c.) to induce PAH. The MCT-treated animals were sacrificed 4 weeks after the treatment (MCT group) or prematurely, based on rapid health deterioration, thereby indicating the advanced stage of PAH (ptMCT group). Pulse oximetry, gravimetry and evaluation of myocardial damage markers were used to assess the development of PAH. The molecular analyses (ELISA, RT-qPCR and immunoblotting) were used to examine the potential underlying mechanisms of tissue damage due to cell death. Results In the RVs, the expression of both pThr231/Ser232-RIP3 and pSer345-mixed linkage kinase domain-like protein was elevated equally in both PAH stages, strongly indicating promotion of necroptosis. Contrary in the lungs affected by PAH, the upregulation of pThr231/Ser232-RIP3 likely proceeded to pyroptotic rather than necroptotic cell death activation, as evidenced by caspase-1 and N-terminal gasdermin D increase. Moreover, we found that the plasma RIP3 levels increased with the severity of PAH stage and positively correlated with RV hypertrophy, but not with cardiac hemodynamic stress markers. Conclusions In summary, we showed for the first time that PAH-induced damage of RV and lung tissue might be mediated by different necrosis-like cell death forms with a crucial role pThr231/Ser232-RIP3. Furthermore, we suggested that the plasma RIP3 might serve as an additional diagnostic and prognostic marker of cardiac damage due to PAH.
Improving Treatment Approaches for Rectal Cancer
Authors: Hanna K. Sanoff
Journal: New England Journal of Medicine (2022)

The cure rate for nonmetastatic rectal cancer has been improving for decades. Treatment for stage II and III rectal adenocarcinomas now routinely includes surgery, radiation therapy, and chemotherapy. The results of recent phase 3 trials have led to an increase in the intensity of treatment to include multiagent chemotherapy in addition to radiation therapy before proctectomy is performed; such treatment has resulted in a 3-year disease-free survival rate as high as 77%.1,2 Unfortunately, this treatment approach is grueling and can cause substantial long-term sequelae, including neuropathy, infertility, and bowel and sexual dysfunction. However, this more aggressive preoperative treatment also opens . . .
MODL-26. Development of humanized immune system, posterior fossa A ependymoma patient-derived xenograft model
Authors: Andrea Griesinger, Julie Lang, Andrew Donson, Enrique Grimaldo, Angela Pierce, Aaron Knox, Jenna Steiner, Natalie Serkova, Timothy Ritzmann, Richard Grundy, Nicholas Foreman
Journal: Neuro-Oncology (2022)

Abstract Cellular interactions between tumor and immune cells are critical in ependymoma biology. We have shown distinct immunobiology phenotypes by ependymoma molecular subgroups, with PFA2 developing an anti-tumor immune phenotype and in contrast PFA1 tumor immune cells being pro-tumor. We recently established two fully characterized pediatric PFA1 intracranial xenograft models in NSG mice. These models, while critical for advancing PFA studies, lack the ability to make lymphocytes. To address this we have established a humanized orthotopic model of PFA1 ependymoma that are grafted to produce functional human lymphocytes. To do this, CD34+ human umbilical cord blood was injected into the cranial facial vein of newborn, irradiation immunodepleted, BRGS mice. Human immune chimerism was determined at 10 weeks by flow cytometry of peripheral blood. Next, we injected existing PDX model MAF-928_XF cells into the 4th ventricle at 12 weeks age and tumors were monitored by MRI. Initial scanning found the tumors were delayed in developing, consistent with other humanized solid tumor mouse models. Mice were euthanized between 32-34 weeks age and necropsies were performed to isolate brain, lymph nodes, blood and spleen. Human chimerism was detectable, by flow cytometry, in spleen, lymph nodes and blood, and most cells were T-cells. Human T-cells were detectable in all tumors, in proportions consistent with human disease (0.05-0.5% of CD45+). Tumors also had 35-50% mouse myeloid infiltration. Tumors were MHC I negative and MHC II positive, and PD-L1 low. Histology was consistent with human ependymoma. We are using spatial proteomics to determine cellular location and phenotype of infiltrating immune cells. Initial studies indicate this model will be usable for modeling the critical tumor-immune interactions and pre-clinically testing the next therapies in PFA ependymoma and can be easily adapted to other pediatric brain tumors in which immune factors have a critical role.
Anti-PD-1 antibody plus regorafenib in refractory microsatellite stable metastatic colorectal cancer: A retrospective study.
Authors: Rongrong Li, Zhenyang Liu, Xianli Yin, Deyu Zeng, Shaofeng Jiang, Liu Wu
Journal: Journal of Clinical Oncology (2022)

e15582 Background: To investigate the efficacy and safety of anti-PD-1 antibody plus regorafenib in refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Methods: We retrospectively analyzed the efficacy and safety of 103 MSS mCRC patients treated with anti -PD-1 antibodies(including nivolumab, pembrolizumab, camrelizumab, sintilimab, and toripalimab) combined with regorafenib(80 mg once daily for 21 days on/7 days off)between July 2019 and June 2021 in Hunan Cancer Hospital. Results: 103 patients had received at least one dose of regorafenib plus anti -PD-1 antibody. Due to COVID-19 pandemics, economic or other reasons, 48 patients (46.6%) did not return to hospital for second cycle of combination treatment .With a median follow-up of 5.30 months (range 0.50-22.50), the median overall survival (mOS) and progression-free survival (mPFS) were 8.40 months (95%CI:6.40-12.70) and 2.50 months (95%CI:2.27-3.47) in the entire cohort, respectively. The mOS and mPFS were significantly longer in patients who received more than 1 cycle (n = 55, 53.4%) compared to those who received just 1 cycle(n = 48, 46.6%). (16.07 vs. 4.37 months, HR 0.21; 95%CI:[0.12-0.38]； P﹤0.001; 3.10 vs. 1.11 months, HR 0.12; 95%CI: [0.05-0.31];P﹤0.001). Further analyses revealed that sintilimab (n = 66, 64.1%) significantly improved mPFS from 1.61 months to 3.30 months, compared to other anti-PD-1 antibodies (n = 37, 35.9%) (HR 0.55; 95%CI:[0.31-0.99];P = 0.044). Cox multivariate regression analysis demonstrated that cycles of regorafenib plus PD-1 was a significant independent risk factor for the OS and PFS( P0.001).Patients who had previously undergone surgery were better than those who had not ( P= 0.029).Sintilimab plus regorafenib had a better PFS benefit( P= 0.044.)Seven patients were diagnosed as partial response and another 16 cases were diagnosed as stable disease in the 55 patients who were evaluated, but no complete response. Thus the objective response rate was 12.7% and the disease control rate was 41.8%.Treatment-related adverse events of grade 3 or higher occurred in 13 (12.6%) patients. Conclusions: The combination of regorafenib plus anti-PD-1 antibody had a manageable safety profile and promising efficacy in MSS mCRC patients, especially in patients who received more than one cycle. Compared with the other anti-PD-1 antibodies, sintilimab may have more encouraging efficacy, which needs further prospective studies.[Table: see text]